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Abstract & Commentary
Source: Gironell A, et al. A randomized placebo-controlled comparative trial of gabapentin and propranolol in essential tremor. Arch Neurol 1999;56:475-480.
Essential tremor (et), one of the most common movement disorders, is characterized by tremor during the maintenance of posture and active movement. Although ET is commonly perceived to be benign, some patients suffer significant disability, and a larger number suffer substantial embarrassment.
The efficacy of primidone and B-adrenergic antagonists (e.g., propanolol) has been demonstrated, but many patients fail to respond, suffer intolerable side effects, or have contraindications to these medications. Previously, an open-label trial of gabapentin (Neurontin) suggested efficacy for ET,1 but a double-blind, placebo-controlled study of adjunctive gabapentin in 20 patients found no improvement at a dose of 1800 mg/d compared to placebo.2 The current study was undertaken in the neurology clinic in Barcelona, Spain. Sixteen patients with moderate to severe bilateral ET and no other neurological disorders were enrolled. Exclusion criteria included cardiac failure, asthma, peripheral vascular disease, diabetes mellitus, and active treatment with tremor-inducing or alleviating drugs.
After a two-week washout period, participants were given gabapentin 400 mg tid or propranolol 40 tid for two weeks in a double-blind, placebo-controlled, crossover trial. A one-week washout period occurred between treatments. Assessment measures included the Tremor Clinical Rating Scale (TCRS), accelerometric (neurophysiological) recordings done on the index finger of the most affected hand, and a 25-item self-reported disability scale. The TCRS includes four examinations rated on a 0-4 scale: 1) tremor of the hands, legs, head, and trunk; 2) motor task performance; 3) functional disability; and 4) subjective assessment by the patient. Analysis of variance (ANOVA) was used to test the effect of medication on tremor. Paired comparisons were analyzed by the test after control for inflation type I errors.
A statistically significant treatment effect was shown for gabapentin and propranolol compared to placebo with regard to tremor, motor task performance, functional disability, and subjective assessment by the patient on the TCRS. No statistical differences were found between gabapentin, propranolol, and placebo in terms of the accelerometric (neurophysiological) recordings; baseline variability may have been too great to see a treatment effect. In terms of the self-reported disability scale, neither drug was statistically better than placebo. All patients completed the study; no serious adverse events occurred. Limitations included a small sample size, fixed dosing (which limited meaningful titration), performing accelerometric recordings only on the most affected hand (potential bias, rather than an average of both hands), and a single study site (which limits generalization of the results).
Comment by Donald M. Hilty, MD
The origin of ET is unknown. A central mechanism involving the inferior olive is incriminated by most experimental data,3 though some modulation may occur from the cerebellum, thalamus, motor cortex, and brainstem nuclei.4 Gabapentin may work by increasing gamma-aminobutyric acid (GABA) levels and reducing intracortical excitability. Gabapentin is extremely well tolerated, even in geriatric patients.5 A large, multicenter trial is indicated to further study gabapentin for ET.
1. Burrows GT, King RB. Gabapentin in essential tremor. Neurology 1995;45(suppl 4):A187-188.
2. Pahwa R, et al. Double-blind placebo controlled study of gabapentin in essential tremor. Mov Disord 1998; 13:465-467.
3. Elble RJ. Central mechanisms of tremor. J Clin Neurophysiol 1996;13:133-144.
4. Lamarre Y. Tremorgenic mechanisms in primates. Adv Neurol 1975;10:23-34.
5. Handforth A, Trieman DM. Efficacy and tolerance of long-term, high-dose gabapentin: Additional observations. Epilepsia 1994;35:1032-1037.